A number of patents disclose transdermal or buccal dosage forms containing testosterone and include cast and extruded films, including U.S. Pat. No. 6,585,997 (U.S. Pregrant Patent Application Publication No. 20030044446) to Moro et al. (Access Pharmaceuticals); U.S. Pat. No. 6,562,369 to Luo et al. (Dermatrends Inc.); U.S. Pat. No. 6,555,131 to Wolff et al. (Schwarz Pharma AG); U.S. Pat. No. 6,010,715, U.S. Pat. No. 5,679,373, U.S. Pat. No. 5,662,926, and U.S. Pat. No. 5,676,969 to Wick et al. (Bertek Inc.); and PCT International Patent Application Publication No. WO 00/19975.
Many researchers have utilized hot-melt extrusion techniques to produce pharmaceutical preparations in various forms, including films. Aitken-Nichol et al. (Aitken-Nichol, C., F. Zhang, and J. W. McGinity, Hot Melt Extrusion of Acrylic Films. Pharmaceutical Research, 1996. 13(5): p. 804-808) used hot-melt extrusion methods to produce acrylic polymer films containing the active lidocaine HCl. Grabowski et al. (Grabowski, S., et al., Solid active extrusion compound preparations containing low-substituted hydroxypropylcellulose. 1999: U.S. Pat. No. 5,939,099 WO9625151 DE19504832 EP0809488) produced solid pharmaceutical preparations of actives in low-substituted hydroxypropyl cellulose using hot-melt extrusion techniques. Repka and McGinity (Repka, M. A. and J. W. McGinity, Hot-melt extruded films for transmucosal & transdermal drug delivery applications. Drug Delivery Technology, 2004. 4(7): p. 40, 42, 44-47) used hot-melt extrusion processes to produce bioadhesive films for topical and mucosal adhesion applications for controlled drug delivery to various mucosal sites (Repka, M. A., S. L. Repka, and J. W. McGinity, Bioadhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery and process for preparation thereof. Apr. 23, 2002: U.S. Pat. No. 6,375,963).
Lamination of solidified or semi-solidified extruded films is known in the polymer processing industry. Lamination is generally considered a two-step process wherein two extrudates are first prepared individually, albeit simultaneously or sequentially, thereby forming solidified or semi-solidified (softened but no molten) extrudates. The extrudates are then laminated using a conventional lamination process. Such processes typically require the use of an adhesive between the solid or semi-solid layers followed by pressing them together and/or the application of heat and pressure to the layers by passing them simultaneously through heated rollers (For example, see U.S. Pat. No. 5,700,478, U.S. Pat. No. 5,851,551, U.S. Pat. No. 5,998,431). The lamination process can be done immediately after extrusion or some period of time afterwards.
Coextrusion is a process whereby two or more material feed streams, at least one of which is molten, are brought together and placed in contact with one another prior to exiting through an extrusion die. In one process, both material feed streams are molten prior when they are placed in contact with one another. In an alternate process, one material feed stream is molten and the second material feed stream is a preformed solid or semi-solid extrudate onto which the first material is placed prior to extrusion through a die. Coextrusion can be achieved using different types of dies: a dual manifold (or multi-manifold) die or a feed block die assembly, each of which is described below.
European Patent Application EP 1493561 (U.S. Pat. No. 6,638,637) discloses the preparation of a bilayered film by coextrusion of a primary layer containing propylene copolymer with a secondary layer containing propylene copolymer or homopolymer. The melting point of the two layers is different.
U.S. Pat. No. 6,753,370 (Japanese patent application no. JP 09327851) discloses the preparation of a bilayered film by coextrusion of a polyamide (PA) resin with a saponified ethylene-vinyl acetate (EVOH) copolymer such that the melt viscosity of the PA resin is greater than that of the EVOH copolymer.
U.S. Pregrant patent application publication no. 2003000501 discloses a method of preparing a multi-layered adhesive film wherein an adhesive composition containing an amine-modified, low acid ethylene-methacrylic acid copolymer having a specified melt index is coextruded with an aliphatic polyketone copolymer.
Blatz (PAP. FILM FOIL CONVERTER, vol 53 no 1 Jan. 1979 pp 102-104) discloses a method of employing interlaminar adhesives for lamination of films in order to prepare multi-layered films.
U.S. Pat. No. 6,010,715, U.S. Pat. No. 5,679,373, U.S. Pat. No. 5,662,926, and U.S. Pat. No. 5,676,969 to Wick et al. (Bertek Inc.) discloses a transdermal patch “for the controlled release of an active agent to the skin or mucosa of a host. The patches are laminates of a backing layer and a monolithic carrier layer formed from a melt blend of an active ingredient with a thermoplastic matrix polymer.
U.S. Pat. No. 6,375,963 to Repka et al. discloses a bioadhesive hot-melt extruded mono-layered or multi-layered film composition comprising a water swellable or water soluble thermoplastic polymer and a bioadhesive polymer optionally containing an organic acid, a superdisintegrant, a super-absorbent and/or an antioxidant.
U.S. Pat. No. RE 33,093 to Schiraldi et al. describes a bioadhesive hot-melt extruded film for intra-oral drug delivery and the processing thereof. The film comprises essentially a bioadhesive layer consisting of 40-95% by weight of a hydroxypropylcellulose (HPC), 5-60% of a homopolymer of ethylene oxide (PEO), 0-10% of a water-insoluble polymer, a medicament and 2-10% of a plasticizer. The film is made by a hot-melt extrusion process. A multi-layered film can be made.
U.S. Pat. No. 6,072,100 to Mooney et al. discloses an extruded composition containing “a thermoplastic water-soluble polymer selected from the group consisting of hydroxypropyl cellulose and polyethylene oxide; a water-soluble polymer derived from acrylic acid; medicament; and plasticizer.” They disclose a mono-layered or multi-layered composition.
PCT International Patent Publication No WO 99/13812 to Moo-Young et al. (The Population Council) discloses a melt-extruded transdermal formulation for the delivery of an androgen via the skin or mouth.
However, prior art processes for the preparation of heat laminated multi-layered laminates via hot-melt coextrusion often result in the formation of non-uniform laminates. Such films have a non-uniform transverse cross-section, meaning that the transverse cross-section of the laminate varies along the longitudinal axis of the laminate as it is produced by coextrusion. Non-uniformity is highly undesirable in the pharmaceutical industry as it leads to variable dosage strength from one unit dose to another.
None of these references describe a hot-melt coextruded laminate, and process therefor, possessing the advantageous properties as described herein.